Hydrogels for delivery of therapeutic compounds
In some aspects, methacrylate co-polymers crosslinked with an enzymatically cleavable peptide linker are provided and may be used for the oral delivery of a therapeutic. The peptide linker may be cleavable by an enzyme in the small intestine and may allow for the delivery of a therapeutic protein or nucleic acid to the small intestine. Also provided are methods of using the polymers for the treatment of a disease.
1. A method for loading a nucleic acid into a copolymer, comprising:
(i) incubating a copolymer comprising an acrylic acid, an acrylate monomer, or methacrylic acid in a loading solution comprising the nucleic acid: and subsequently
(ii) crosslinking the copolymer with a crosslinker;
wherein the crosslinker comprises GRRRGK (SEQ ID NO: 1).
2. The method of claim 1 , wherein the crosslinker is an enzymatically cleavable peptide crosslinker.
3. The method of claim 2 , wherein the copolymer comprises methacrylic acid and N-vinylpyrrolidone.
4. The method of claim 1 , wherein the nucleic acid is a siRNA, an miRNA, or an shRNA.
5. The method of claim 1 , wherein the copolymer is a P(MAA-co-NVP) copolymer; and wherein the crosslinker is an enzymatically cleavable peptide linker, wherein the peptide linker is 6-25 amino acid residues in length and contains at least one lysine amino acid.
6. The method of claim 2 , wherein the peptide crosslinker is 6-20 amino acid residues in length.
7. The method of claim 1 , wherein the hydrogel polymer comprises the structure:
8. The method of claim 2 , wherein the polymer is crosslinked with the peptide through the use of a coupling reagent.
9. The method of claim 8 , wherein the coupling reagent is a carbodiimide.
10. The method of claim 2 , wherein the polymer is crosslinked with the peptide via an EDC-NHS reaction.
11. A method for loading a nucleic acid into a copolymer, comprising:
(i) incubating a copolymer comprising an acrylic acid, an acrylate monomer, or methacrylic acid in a loading solution comprising the nucleic acid; and subsequently
(ii) crosslinking the copolymer with a crosslinker;
wherein the crosslinker comprises the structure:
12. The method of claim 11 , wherein the crosslinker is an enzymatically cleavable peptide crosslinker.
13. The method of claim 12 , wherein the copolymer comprises methacrylic acid and N-vinylpyrrolidone.
14. The method of claim 11 , wherein the nucleic acid is a siRNA, an miRNA, or an shRNA.
15. The method of claim 11 , wherein the copolymer is a P(MAA-co-NVP) copolymer; and wherein the crosslinker is an enzymatically cleavable peptide linker, wherein the peptide linker is 6-25 amino acid residues in length and contains at least one lysine amino acid.
16. The method of claim 12 , wherein the peptide crosslinker is 6-20 amino acid residues in length.
17. The method of claim 11 , wherein the copolymer comprises the structure:
18. The method of claim 12 , wherein the copolymer is crosslinked with the peptide through the use of a coupling reagent.
19. The method of claim 18 , wherein the coupling reagent is a carbodiimide.
20. The method of claim 12 , wherein the copolymer is crosslinked with the peptide via an EDC-NHS reaction.